US5371094A - Azaheterocyclylmethyl-chromans for treating axiety - Google Patents

Azaheterocyclylmethyl-chromans for treating axiety Download PDF

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US5371094A
US5371094A US07/984,076 US98407692A US5371094A US 5371094 A US5371094 A US 5371094A US 98407692 A US98407692 A US 98407692A US 5371094 A US5371094 A US 5371094A
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carbon atoms
chain
branched alkyl
straight
chroman
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Hans-Georg Heine
Rudolf Schohe-Loop
Thomas Glaser
Jean M. V. De Vry
Wolfgang Dompert
Henning Sommermeyer
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Bayer AG
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Bayer AG
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Assigned to BAYER AG reassignment BAYER AG ASSIGNMENT OF ASSIGNORS INTEREST. Assignors: DE VRY, JEAN MARIE VIKTOR, DOMPERT, WOLFGANG, GLASER, THOMAS, HEINE, HANS-GEORG, SCHOHE-LOOP, RUDOLF, SOMMERMEYER, HENNING
Priority to US08/292,639 priority Critical patent/US5545643A/en
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Priority to US08/459,076 priority patent/US5693653A/en
Priority to US08/460,475 priority patent/US5696137A/en
Priority to US08/459,071 priority patent/US5696136A/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/26—Psychostimulants, e.g. nicotine, cocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • the invention relates to azaheterocyclylmethyl-chromans, processes for their preparation and their use in medicaments, in particular as agents for controlling diseases of the central nervous system.
  • the invention relates to azaheterocyclylmethyl-chromans of the general formula (I), ##STR1## in which A, B and D independently of one another represent hydrogen, halogen, cyano, azido, nitro, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, hydroxyl or carboxyl, or
  • alkyl represent straight-chain or branched alkyl, alkenyl, acyl or alkoxycarbonyl having, in each case, up to 8 carbon atoms, or
  • R 1 , R 2 and R 3 are identical or different and denote hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms, phenyl or benzyl,
  • L denotes the --CO-- or --SO 2 -- group
  • R 4 denotes straight-chain or branched alkyl having up to 8 carbon atoms or benzyl, or denotes aryl having 6 to 10 carbon atoms, which is optionally substituted by halogen, hydroxyl, nitro, cyano, trifluoromethyl or trifluoromethoxy or by straight-chain or branched alkyl or alkoxy having up to 6 carbon atoms, and
  • R 5 denotes straight-chain or branched alkyl or alkenyl having, in each case, up to 8 carbon atoms, which are optionally substituted by cycloalkyl having 3 to 6 carbon atoms or phenyl,
  • A has one of the abovementioned meanings
  • R 6 denotes hydrogen, hydroxyl, halogen or phenyl
  • R 7 and R 8 independently of one another denote a straight-chain or branched alkyl having up to 8 carbon atoms, which must be substituted by a radical of the formula ##STR4## or denote a radical of the formula ##STR5## and R 9 denotes hydrogen, halogen, cyano, nitro, trifluoromethyl, trifluoromethoxy, hydroxyl or straight-chain or branched alkyl or alkoxy having, in each case, up to 6 carbon atoms,
  • physiologically acceptable salts are preferred.
  • Physiologically acceptable salts of the compounds according to the invention can be salts of the substances according to the invention with inorganic acids, carboxylic acids or sulphonic acids.
  • Particularly preferred salts are, for example, salts with hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, ethanesulphonic acid, toluenesulphonic acid, benzenesulphonic acid, naphthalenedisulphonic acid, acetic acid, propionic acid, lactic acid, tartaric acid, citric acid, fumaric acid, maleic acid or benzoic acid.
  • Heterocycle in general represents a 5-membered to 7membered, preferably 5-membered to 6-membered, saturated or unsaturated ring, which can contain up to 2 oxygen, sulphur and/or nitrogen atoms as hetero atoms. 5-membered and 6-membered rings containing one oxygen, sulphur and/or up to 2 nitrogen atoms are preferred.
  • the compounds according to the invention can be present in various stereoisomeric forms.
  • the compounds according to the invention exist in stereoisomeric forms which are either related to one another as image and mirror image (enantiomers) or are not related to one another as image and mirror image (diastereoisomers).
  • the invention relates both to the antipodes and the racemic forms and to the mixtures of diastereoisomers.
  • the racemic forms can be separated in the same way as the diastereoisomers in a known manner into the single stereoisomer constituents [compare E.L. Eliel, Stereochemistry of Carbon Compounds, McGraw Hill, 1962].
  • Preferred compounds of the general formula (I) are those
  • A, B and D independently of one another represent hydrogen, fluorine, chlorine, bromine, cyano, trifluoromethyl, difluoromethoxy, trifluoromethoxy or hydroxyl, or represent straight-chain or branched alkyl, alkenyl, acyl or alkoxycarbonyl having, in each case, up to 6 carbon atoms, or represent a group of the formula --NR 1 R 2 --NR 3 --L--R 4 or --OR 5 ,
  • R 1 , R 2 and R 3 are identical or different and denote hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms,
  • L denotes the --CO-- or --SO 2 -- group
  • R 4 denotes straight-chain or branched alkyl having up to 6 carbon atoms or benzyl, or denotes phenyl which is optionally substituted by fluorine, chlorine, bromine, trifluoromethyl, trifluoromethoxy or hydroxyl or by straight-chain or branched alkyl or alkoxy having, in each case, up to 4 carbon atoms, and
  • R 5 denotes straight-chain or branched alkyl or alkenyl having up to 6 carbon atoms, which are optionally substituted by cyclopropyl, cyclopentyl, cyclohexyl or phenyl,
  • A has one of the abovementioned meanings
  • R 6 denotes hydrogen, hydroxyl, fluorine, chlorine, bromine or phenyl
  • R 7 and R 8 independently of one another denote straight-chain or branched alkyl having up to 6 carbon atoms, which must be substituted by a radical of the formula ##STR8## or denote a radical of the formula ##STR9##
  • R 9 denotes hydrogen, fluorine, chlorine, bromine, trifluoromethyl, hydroxyl or straight-chain or branched alkyl or alkoxy having, in each case, up to 4 carbon atoms
  • A, B and D independently of one another represent hydrogen, fluorine, chlorine, bromine, cyano, trifluoromethyl, trifluoromethoxy or hydroxyl, or represent straight-chain or branched alkyl or alkenyl having, in each case, up to 4 carbon atoms, or represent a group of the formula --NR 1 R 2 or --OR 5 ,
  • R 1 and R 2 are identical or different and denote hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms, and
  • R 5 denotes straight-chain or branched alkyl or alkenyl having up to 4 carbon atoms, which are optionally substituted by cyclopropyl or phenyl,
  • A has one of the abovementioned meanings
  • E represents a heterocyclic radical of the formula ##STR11## wherein R 6 denotes hydrogen, hydroxyl, fluorine or chlorine,
  • R 7 and R 8 independently of one another denote straight-chain or branched alkyl having up to 4 carbon atoms, which must be substituted by a radical of the formula ##STR12##
  • R 9 denotes hydrogen, fluorine, chlorine, trifluoromethyl, hydroxyl, methyl, ethyl, methoxy or ethoxy,
  • Y represents hydroxyl or represents a typical leaving group, such as, for example, tosylate, chloride or mesylate, preferably tosylate,
  • T denotes straight-chain or branched alkyl having up to 8 carbon atoms
  • R 10 represents one of the heterocyclic radicals mentioned above under R 7 ,
  • R 10 has the abovementioned meaning
  • substituents A, B and D are converted to derivatives, likewise by known methods.
  • Suitable solvents for the reaction with the amines of the general formula (III) are the conventional solvents which do not change under the reaction conditions. These preferably include alcohols, such as methanol, ethanol, propanol or isopropanol, or ethers, such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or butyl methyl ether, or ketones, such as acetone or butanone, or amides, such as dimethylformamide or hexamethylphosphoric acid triamide, or dimethylsulphoxide, acetonitrile, ethyl acetate or halogenated hydrocarbons, such as methylene chloride, chloroform or carbon tetrachloride, or pyridine, picoline or N-methylpiperidine. Mixtures of the said solvents can also be used. Methanol, ethanol, propanol, isopropanol or dimethylformamide are preferred.
  • Suitable bases are the conventional inorganic or organic bases. These preferably include alkali metal hydroxides, such as sodium hydroxide or potassium hydroxide, or alkali metal carbonates, such as sodium carbonate or potassium carbonate, or alkali metal alcoholates, such as, for example, sodium methanolate, potassium methanolate, sodium ethanolate or potassium ethanolate, or organic amines, such as triethylamine, picoline, pyridines or N-methylpiperidine, or amides, such as sodium amide or lithium diisopropylamide.
  • alkali metal hydroxides such as sodium hydroxide or potassium hydroxide
  • alkali metal carbonates such as sodium carbonate or potassium carbonate
  • alkali metal alcoholates such as, for example, sodium methanolate, potassium methanolate, sodium ethanolate or potassium ethanolate
  • organic amines such as triethylamine, picoline, pyridines or N-methylpiperidine
  • amides such as sodium amide
  • the bases are used in an amount of 0.5 mol to 10 mols, preferably of 0.3 mol to 3 mols, based on 1 mol of the compounds of the general formula (II). In the case of pyridine, the base can also be used as solvent.
  • the reaction is generally carried out in a temperature range of 0° C. to 150° C., preferably of +20° C. to +110° C.
  • the reaction can be carried out under normal, elevated or reduced pressure (for example 0.5 to 5 bar). In general the reaction is carried out under normal pressure.
  • the reductions can in general be carried out by hydrogen in water or in inert organic solvents, such as alcohols, ethers or halogenated hydrocarbons, or mixtures thereof, using catalysts such as Raney nickel, palladium, palladium-on-animal charcoal or platinum, or using hydrides or boranes in inert solvents, if appropriate in the presence of a catalyst.
  • inert organic solvents such as alcohols, ethers or halogenated hydrocarbons, or mixtures thereof
  • catalysts such as Raney nickel, palladium, palladium-on-animal charcoal or platinum, or using hydrides or boranes in inert solvents, if appropriate in the presence of a catalyst.
  • the reaction is preferably carried out using hydrides, such as complex borohydrides or aluminium hydrides.
  • hydrides such as complex borohydrides or aluminium hydrides.
  • sodium borohydride, lithium aluminium hydride or sodium cyanoborohydride are particularly preferably employed.
  • Suitable solvents in this context are all inert organic solvents which do not change under the reaction conditions. These preferably include alcohols, such as methanol, ethanol, propanol or isopropanol, or ethers, such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, or amides, such as hexamethylphosphoric acid triamide or dimethylformamide, or acetic acid. It is also possible to use mixtures of the said solvents.
  • alcohols such as methanol, ethanol, propanol or isopropanol
  • ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether
  • amides such as hexamethylphosphoric acid triamide or dimethylformamide, or acetic acid. It is also possible to use mixtures of the said solvents.
  • the catalysts used in the reduction with sodium cyanoborohydride are in general protic acids. These preferably include inorganic acids, such as, for example, hydrochloric acid or sulphuric acid, or organic carboxylic acids having 1-6 C atoms, optionally substituted by fluorine, chlorine and/or bromine, such as, for example, acetic acid, trifluoroacetic acid, trichloroacetic acid or propionic acid, or sulphonic acids containing C 1 -C 4 -alkyl radicals or aryl radicals, such as, for example, methanesulphonic acid, ethanesulphonic acid, benzenesulphonic acid or toluenesulphonic acid.
  • inorganic acids such as, for example, hydrochloric acid or sulphuric acid, or organic carboxylic acids having 1-6 C atoms, optionally substituted by fluorine, chlorine and/or bromine, such as, for example, acetic acid, trifluoroace
  • the Mitsunobu reaction generally proceeds in one of the non-protic solvents indicated above, preferably tetrahydrofuran, in the presence of phosphanes, preferably triphenylphosphane, and ester derivatives of azodicarboxylic acid, preferably diethyl azodicarboxylate, in a temperature range of 0° C. to +50° C., preferably at room temperature and normal pressure [in this context compare O. Mitsunobu, Synthesis 1981,1].
  • the compounds of the general formula (II) are known per se or can be prepared by conventional methods [compare German Patent Specification 3 620 408 A, U.S. Pat. No. 4 957 928, Farmaco, Ed. Sci. 42 (11), 805-813], it being possible to obtain compounds in the form of a single enantiomer by using the corresponding chroman-2-carboxylic acids in the form of a single enantiomer and their derivatives for the preparation [in this context compare J. Labelled Comp. Pharm. 24, 909, 1987].
  • the amines of the general formula (III) are known, can be prepared by conventional methods or are available commercially [compare MSD Book 2, 2846 D; Beilstein 21 (2) 8].
  • R 11 represents C 1 -C 4 -alkyl.
  • the reduction of the acid amides and imides is effected using hydrides in inert solvents or using boranes, diboranes or their complex compounds.
  • the reactions are preferably carried out using hydrides, such as complex borohydrides or aluminiumhydrides, as well as boranes.
  • hydrides such as complex borohydrides or aluminiumhydrides, as well as boranes.
  • sodium borohydride, lithium aluminium hydride, sodium bis-(2-methoxyethoxy)aluminium hydride or borane-tetrahydrofuran are particularly preferably employed.
  • the reaction can be carried out under normal, elevated or reduced pressure (for example 0.5 to 5 bar). In general the reaction is carried out under normal pressure.
  • the reduction is in general effected in a temperature range of -50° C. up to the boiling point of the particular solvent, preferably of -20° C. to +90° C.
  • the compounds of the general formula (VI) are known in some cases or are novel and can be prepared, for example, by reacting the corresponding activated chroman-2-carboxylic acid derivatives with piperidine-4-carboxylic acid esters in inert solvents, preferably pyridine, in the presence of one of the abovementioned bases, preferably pyridine.
  • the compounds according to the invention can be used as active compounds in medicaments.
  • the substances according to the invention have a particularly high affinity for cerebral 5-hydroxy-tryptamine receptors of the 5-HT 1 type. They also have high affinity for dopamine receptors of the D 2 type.
  • the substances according to the invention surprisingly show an advantageous effect on the central nervous system and can be used for the therapeutic treatment of humans and animals.
  • the compounds described in the present invention are thus active compounds for controlling diseases which are characterised by disorders of the serotoninergic and dopaminergic system, in particular in the case of the involvement of receptors which have high affinity for 5-hydroxytryptamine (5-HT 1 type) and/or for dopamine (D 2 type). They are therefore suitable for the treatment of diseases of the central nervous system, such as anxiety, stress and depressive states, sexual dysfunctions related to the central nervous system and sleep disorders, and for regulating pathological disorders of food, coffee, tea, tobacco, alcohol and addictive drug intake. They are also suitable for the elimination of cognitive deficits, for the improvement of learning and memory performance and for the treatment of Alzheimer's disease. They are also suitable for controlling psychoses (for example schizophrenia, mania). Compared with known neuroleptic agents, they have a lower potential for side effects.
  • active compounds are also suitable for modulation of the cardiovascular system. They also intervene in regulation of the cerebral circulation and are thus effective agents for controlling migraine.
  • the compounds are also suitable for the prophylaxis and control of the consequences of cerebral infarct events (apoplexia cerebri), such as stroke and cerebral ischaemias.
  • the compounds can be used for the treatment of acute craniocerebral trauma.
  • the compounds according to the invention can also be used to control states of pain.
  • the high affinity of the compounds according to the invention for 5-hydroxytryptamine receptors of subtype 1 is shown in Table 1 by way of example.
  • the values shown are data which have been determined from receptor-binding studies using calf hippocampus membrane preparations. To this end, aH-serotonin was used as radioactively labelled ligand.
  • the present invention also includes pharmaceutical preparations which contain, in addition to inert, nontoxic, pharmaceutically suitable auxiliaries and excipients, one or more compounds of the general formula (I), or which consist of one or more active compounds of the formula (I), as well as processes for the production of these preparations.
  • the active compounds of the formula (I) should be present in these preparations in a concentration of 0.1 to 99.5% by weight and preferably of 0.5 to 95% by weight of the total mixture.
  • the pharmaceutical preparations can also contain other pharmaceutical active compounds.
  • the abovementioned pharmaceutical preparations can be prepared in a conventional manner by known methods, for example using the auxiliary or auxiliaries or excipient(s).
  • the active compound or active compounds of the formula (I) in total amounts of about 0.01 to about 100 mg/kg, preferably in total amounts of about 1 mg/kg to 50 mg/kg of body weight per 24 hours, optionally in the form of several single doses, in order to achieve the desired results.
  • the R f values mentioned in each case were determined by thin layer chromatography on silica gel (aluminiumfoil, silica gel 60 F 254, E. Merck). The substance spots were visualised by observing under UV light and/or by spraying with 1% strength potassium permanganate solution.
  • This material is further used without further purification.
  • Example III The title compound from Example III is prepared analogously to the method of Example IV.
  • the oxalate which is accessible by adding oxalic acid dihydrate in ethanolic soluticn, is recrystallised from acetonitrile. Further recrystallisation from 2-propanol yields 0.30 g of analytically pure title compound after cooling to -36° C.

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US07/984,076 1991-12-09 1992-11-30 Azaheterocyclylmethyl-chromans for treating axiety Expired - Lifetime US5371094A (en)

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US08/292,639 US5545643A (en) 1991-12-09 1994-08-18 Azaheterocyclylmethyl-chromans
US08/459,076 US5693653A (en) 1991-12-09 1995-06-02 Method of treating depression using azaheterocyclylmethyl-chromans
US08/460,475 US5696137A (en) 1991-12-09 1995-06-02 Azaheterocyclymethyl-chromans
US08/459,071 US5696136A (en) 1991-12-09 1995-06-02 Method of treating psychosis using azaheterocyclylmethyl

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DE4140540 1991-12-09

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US08/459,071 Expired - Fee Related US5696136A (en) 1991-12-09 1995-06-02 Method of treating psychosis using azaheterocyclylmethyl
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US08/459,076 Expired - Fee Related US5693653A (en) 1991-12-09 1995-06-02 Method of treating depression using azaheterocyclylmethyl-chromans
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US6096763A (en) * 1995-02-23 2000-08-01 Merck & Co., Inc. α1a adrenergic receptor antagonists
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US5696137A (en) 1997-12-09
EP0546388A1 (de) 1993-06-16
DE59205846D1 (de) 1996-05-02
CZ283680B6 (cs) 1998-06-17
NZ245381A (en) 1995-03-28
RU2089549C1 (ru) 1997-09-10
US5696136A (en) 1997-12-09
US5693653A (en) 1997-12-02
NO924546D0 (no) 1992-11-25
HUT65427A (en) 1994-06-28
CA2084542A1 (en) 1993-06-10
TW210339B (enrdf_load_stackoverflow) 1993-08-01
JPH05279357A (ja) 1993-10-26
PH31072A (en) 1998-02-05
DE4140540A1 (de) 1993-06-17
SK278553B6 (en) 1997-09-10
AU650182B2 (en) 1994-06-09
JP3220266B2 (ja) 2001-10-22
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NO303174B1 (no) 1998-06-08
GR3019450T3 (en) 1996-06-30
FI925549L (fi) 1993-06-10
DK0546388T3 (da) 1996-07-29
AU2993892A (en) 1993-06-10
HU9203894D0 (en) 1993-03-29
EP0546388B1 (de) 1996-03-27
US5545643A (en) 1996-08-13
ATE136030T1 (de) 1996-04-15
NO924546L (no) 1993-06-10
IL104006A0 (en) 1993-05-13
FI925549A0 (fi) 1992-12-07
IL104006A (en) 1997-02-18
ES2086623T3 (es) 1996-07-01
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SK361392A3 (en) 1997-09-10

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